Department of Biotechnology, National Institute of Pharmaceutical Education and Research - Guwahati, Changsari, India.
Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane and Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Breast Cancer Res Treat. 2024 Oct;207(3):649-663. doi: 10.1007/s10549-024-07398-4. Epub 2024 Jun 14.
Rapid proliferation and nutrition starvation in the tumor microenvironment pose significant challenges to cellular protein homeostasis. The accumulation of misfolded proteins in the endoplasmic reticulum lumen induces stress on cells and causes irreversible damage to cells if unresolved. Emerging reports emphasize the influence of the tumor microenvironment on therapeutic molecule efficacy and treatment outcomes. Hence, we aimed to understand the influence of tamoxifen on the cellular adaptation to endoplasmic reticulum stress during metabolic stress in breast cancer cells.
Nutrition deprivation induces endoplasmic reticulum stress (ER stress), and the unfolded protein response (UPR) in breast cancer cells was confirmed by a Thioflavin B assay and western blotting. Tamoxifen-indued ER-phagy was studied using an MCD assay, confocal microscopy, and western blotting.
Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates the nutrition deprivation-induced endoplasmic reticulum stress through enhancing the selective ER-phagy, a specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation.
Tamoxifen modulates ER stress by inducing ER-phagy through AMPK, thereby, may support breast cancer cell survival during nutrition deprivation conditions.
肿瘤微环境中的快速增殖和营养饥饿对细胞蛋白质稳态构成了重大挑战。内质网腔中错误折叠蛋白的积累会对细胞造成压力，如果得不到解决，会对细胞造成不可逆转的损伤。新的报告强调了肿瘤微环境对治疗分子疗效和治疗结果的影响。因此，我们旨在了解他莫昔芬在营养剥夺诱导内质网应激（ER 应激）和未折叠蛋白反应（UPR）期间对乳腺癌细胞对 ER 应激的细胞适应的影响。
营养剥夺诱导 ER 应激，通过噻唑蓝 B 测定和 Western blot 验证乳腺癌细胞中的未折叠蛋白反应（UPR）。使用 MCD 测定、共聚焦显微镜和 Western blot 研究他莫昔芬诱导的 ER 自噬。
营养剥夺诱导乳腺癌细胞内质网应激。有趣的是，他莫昔芬通过增强选择性 ER 自噬（一种特殊的自噬）来调节营养剥夺诱导的内质网应激。他莫昔芬诱导的 ER 自噬是由 AMPK 激活介导的。AMPK 的药理学抑制可阻断他莫昔芬诱导的 ER 自噬和他莫昔芬在营养剥夺期间对 ER 应激的调节作用。
他莫昔芬通过 AMPK 诱导 ER 自噬来调节 ER 应激，从而在营养剥夺条件下可能支持乳腺癌细胞的存活。
